Risk Factor Management
Is High-Density Lipoprotein Functionality Useful as a Residual Risk Marker for Familial Hypercholesterolemia?
2023 年 87 巻 6 号 p. 813-814
詳細
2023 年 87 巻 6 号 p. 813-814
Familial hypercholesterolemia (FH) is an autosomal dominant inherited metabolic disorder caused by pathological genetic mutations encoding the low-density lipoprotein (LDL) receptor and related molecules. Its frequency is high, occurring in approximately 1 in 300 people in the general population, 1 in 30 people with coronary artery disease (CAD), and 1 in 15 people with premature CAD or severe hypercholesterolemia.1 The risk of CAD is higher in patients with FH,2 and peripheral arterial disease and carotid atherosclerosis are also predominantly prevalent compared with non-FH patients, but it is unclear with regard to stroke.3 Statins are recommended as first-line agents in the treatment of FH, and observational studies have reported that early treatment with statins reduces the incidence of CAD and all-cause death.4
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Not many studies have reported the residual risk after LDL cholesterol-lowering treatment in FH, but high Lp(a), hypertension, and impaired renal function are reported to be risks for CAD in patients with FH diagnosed by genetic testing.5 Japanese observational studies have also shown that hypertension and low high-density lipoprotein (HDL) cholesterol levels are associated with CAD6 and carotid atherosclerosis7 in FH patients on statin therapy. Regarding HDL as a residual risk, its function is considered more attractive than the serum HDL cholesterol level as a residual risk marker, based on a meta-analysis8 showing that additional treatment that increases HDL cholesterol levels in patients on statin therapy does not contribute to CAD prevention.
In this issue of the Journal, Tada et al measured cholesterol uptake capacity (CUC), one of the HDL functions, in 108 clinically diagnosed FH patients and found it more useful than HDL cholesterol levels as a predictive marker of CAD.9 My group also previously reported that cholesterol efflux capacity (CEC), an HDL function, is a more useful predictive marker of CAD than the serum HDL cholesterol level in patients with FH on statin therapy.10
Of the HDL functions, CEC is the one with the most potential for clinical testing,11 but there are several issues with the conventional methods, including the use of radiolabeled cholesterol for the measurement, the use of cultured cells, and the need to correct measurements using pooled plasma/serum from each facility.12 In other words, the conventional method is difficult to perform in hospital due to the complexity of operation, safety, and facilities.
To overcome these issues, researchers in Japan have pioneered the improvement of methods for measuring CEC (Table). For example, Shimizu et al developed a nonradioactive method to quantify the CEC by mass spectrometry using the stable isotope ([d7]-cholesterol) instead of radioactive cholesterol.13 Horiuchi et al developed a cell-free, nonradioactive method to evaluate CEC by fluorescence intensity using gel beads coated with liposomes made from fluorescently labeled cholesterol instead of cells, and showed good correlation with conventional methods.14 Harada et al developed a cell-free, nonradioactive method to evaluate CUC, which showed good correlation with CEC in the conventional method, and also realized the actual phase in an automated analyzer.15 CUC is currently the indicator that is closest to clinical application in HDL function testing.
| Cholesterol efflux capacity (CEC) | Cholesterol uptake capacity (CUC) |
|||
|---|---|---|---|---|
| Name of developers | Rothblat et al11 | Shimizu et al13 | Horiuchi et al14 | Harada et al15 |
| Use of radiolabeled cholesterol | Necessary | Unnecessary | Unnecessary | Unnecessary |
| Use of cultured cells | Necessary | Necessary | Unnecessary | Unnecessary |
| Automated analysis | Not available | Not available | Not available | Available |
| Standardization as a clinical test | Impossible | Impossible | Possible | Possible |
| Study regarding risk assessment of FH | Ogura et al10 | Not yet | Not yet | Tada et al9 |
FH, familial hypercholesterolemia; HDL, high-density lipoprotein.
A critical evaluation of the Tada et al study is that it is inconclusive as to whether CUC is a residual risk marker after LDL cholesterol-lowering treatment, because a significant number of the patients included in the study were untreated. Although multivariate analysis was performed, the clinical backgrounds of the patients with and without CAD should have been better matched. More importantly, there is insufficient discussion on how to take advantage of CUC test results because the CUC result is a phenomenon and not a specific molecule and therefore not a potential therapeutic target.
Despite these criticisms, it should be appreciated that one of the outstanding points of the study by Tada et al is that it demonstrated the potential usefulness of the CUC, a standardizable HDL function test, for risk assessment of FH. In the future, we need to consider how we should manage FH patients with low CUC, whether it is better to further lower LDL cholesterol or to do an intervention trial to increase CUC. Research on the residual risk of FH still has a way to go.
M.O. received lecture fees from Amgen and Kowa.
